Locally Advanced Rectal Cancer Patients Research Articles

Risk-factors for locally advanced rectal cancer relapse after neoadjuvant chemoradiotherapy: A single center experience.

The overall prognosis of locally advanced rectal cancer (LARC) remains unsatisfactory due to a high incidence of disease relapse. The present understanding of the factors that determine the likelihood of recurrence is limited or ineffective. We aimed to identify the main risk factors influencing tumor relapse in LARC patients after neoadjuvant chemoradiotherapy (nCRT) and surgical treatment in a single center in Republika Srpska. Patients with stage II or stage III who received nCRT before surgery for primary rectal cancer at the Oncology Clinic, University Clinical Center of Republika Srpska from January 2017 and December 2022 were included in the study. We collected patient demographics, clinical stage and characteristics, neoadjuvant therapy, and surgical methods, along with the pathological response after treatment completion, and analyzed them to identify the risk factors for tumor relapse. Out of 109 patients diagnosed with LARC, 34 (31,2%) had tumor relapse. The median time to relapse was 54 months. Participants with clinical T4 stage had a significantly shorter relapse time compared to the patients with clinical T2/3 stage. Subjects with positive lymph nodes removed, perivascular and perineural invasion, intraoperative perforation and patients without ypN stage improvement had significantly shorter time to relapse. Subjects with T4 stage had more than 4 times higher risk of relapse than patients with clinical T2/3 stage. Higher clinical T stage was an essential risk factor for tumor relapse in LARC patients after nCRT and surgical treatment. Comprehensive understanding and identification of the risk factors for tumor relapse in LARC patients are crucial for improving their long-term outcomes.

Radiomics Signature Based on Support Vector Machines for the Prediction of Pathological Complete Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer

The objective of this study was to evaluate the discriminative capabilities of radiomics signatures derived from three distinct machine learning algorithms and to identify a robust radiomics signature capable of predicting pathological complete response (pCR) after neoadjuvant chemoradiotherapy in patients diagnosed with locally advanced rectal cancer (LARC). In a retrospective study, 211 LARC patients were consecutively enrolled and divided into a training cohort (n = 148) and a validation cohort (n = 63). From pretreatment contrast-enhanced planning CT images, a total of 851 radiomics features were extracted. Feature selection and radiomics score (Radscore) construction were performed using three different machine learning methods: least absolute shrinkage and selection operator (LASSO), random forest (RF) and support vector machine (SVM). The SVM-derived Radscore demonstrated a strong correlation with the pCR status, yielding area under the receiver operating characteristic curves (AUCs) of 0.880 and 0.830 in the training and validation cohorts, respectively, outperforming the RF and LASSO methods. Based on this, a nomogram was developed by combining the SVM-based Radscore with clinical indicators to predict pCR after neoadjuvant chemoradiotherapy. The nomogram exhibited superior predictive power, achieving AUCs of 0.910 and 0.866 in the training and validation cohorts, respectively. Calibration curves and decision curve analyses confirmed its appropriateness. The SVM-based Radscore demonstrated promising performance in predicting pCR for LARC patients. The machine learning-driven nomogram, which integrates the Radscore and clinical indicators, represents a valuable tool for predicting pCR in LARC patients.

Prediction of Radiation Treatment Response for Locally Advanced Rectal Cancer via a Longitudinal Trend Analysis Framework on Cone-Beam CT.

Locally advanced rectal cancer (LARC) presents a significant challenge in terms of treatment management, particularly with regards to identifying patients who are likely to respond to radiation therapy (RT) at an individualized level. Patients respond to the same radiation treatment course differently due to inter- and intra-patient variability in radiosensitivity. In-room volumetric cone-beam computed tomography (CBCT) is widely used to ensure proper alignment, but also allows us to assess tumor response during the treatment course. In this work, we proposed a longitudinal radiomic trend (LRT) framework for accurate and robust treatment response assessment using daily CBCT scans for early detection of patient response. The LRT framework consists of four modules: (1) Automated registration and evaluation of CBCT scans to planning CT; (2) Feature extraction and normalization; (3) Longitudinal trending analyses; and (4) Feature reduction and model creation. The effectiveness of the framework was validated via leave-one-out cross-validation (LOOCV), using a total of 840 CBCT scans for a retrospective cohort of LARC patients. The trending model demonstrates significant differences between the responder vs. non-responder groups with an Area Under the Curve (AUC) of 0.98, which allows for systematic monitoring and early prediction of patient response during the RT treatment course for potential adaptive management.

Data-Independent Acquisition Mass Spectrometry Analysis of FFPE Rectal Cancer Samples Offers In-Depth Proteomics Characterization of the Response to Neoadjuvant Chemoradiotherapy.

Locally advanced rectal cancer (LARC) presents a challenge in identifying molecular markers linked to the response to neoadjuvant chemoradiotherapy (nCRT). This study aimed to utilize a sensitive proteomic method, data-independent mass spectrometry (DIA-MS), to extensively analyze the LARC proteome, seeking individuals with favorable initial responses suitable for a watch-and-wait approach. This research addresses the unmet need to understand the response to treatment, potentially guiding personalized strategies for LARC patients. Post-treatment assessment included MRI scans and proctoscopy. This research involved 97 LARC patients treated with intense chemoradiotherapy, comprising radiation and chemotherapy. Out of 97 LARC included in this study, we selected 20 samples with the most different responses to nCRT for proteome profiling (responders vs. non-responders). This proteomic approach shows extensive proteome coverage in LARC samples. The analysis identified a significant number of proteins compared to a prior study. A total of 915 proteins exhibited differential expression between the two groups, with certain signaling pathways associated with response mechanisms, while top candidates had good predictive potential. Proteins encoded by genes SMPDL3A, PCTP, LGMN, SYNJ2, NHLRC3, GLB1, and RAB43 showed high predictive potential of unfavorable treatment outcome, while RPA2, SARNP, PCBP2, SF3B2, HNRNPF, RBBP4, MAGOHB, DUT, ERG28, and BUB3 were good predictive biomarkers of favorable treatment outcome. The identified proteins and related biological processes provide promising insights that could enhance the management and care of LARC patients.

THeragnostic utilities for neoplastic DisEases of the rectum by MRI guided radiotherapy (THUNDER 2) phase II trial: interim safety analysis

BackgroundThe THUNDER-2 phase II single institutional trial investigates the benefits of MRI-guided radiotherapy (MRIgRT) in treating locally advanced rectal cancer (LARC). This study focuses on evaluating the impact of escalating radiation therapy dose in non-responder patients using the Early Tumour Regression Index (ERI) for predicting complete response (CR). The trial’s primary endpoint is to increase the CR rate in non-responders by 10% and assess the feasibility of the delta radiomics-based MRIgRT predictive model. This interim analysis assesses the feasibility and safety of the proposed MRIgRT dose escalation strategy in terms of acute toxicity (gastrointestinal, genitourinary and haematological) and treatment adherence.MethodsStage cT2-3, N0-2, or cT4 patients with anal sphincter involvement, N0-2a, M0, but without high-risk features were enrolled. MRIgRT treatment consisted of a standard dose of 55 Gy to the Gross Tumor Volume (GTV) and mesorectum, and 45 Gy to the mesorectum and drainage nodes in 25 fractions with concomitant chemotherapy. 0.35 T MRI was used for simulation imaging and daily alignment. ERI was calculated at the 10th fraction. Non-responders with an ERI above 13.1 received intensified dose escalation from the 11th fraction, resulting in a total dose of 60.1 Gy. Acute toxicity was assessed using the CTCAE v.5 scale.ResultsFrom March 2021 to November 2022, 33 out of the total number of 63 patients to be enrolled (52.4%) were included, with one withdrawal unrelated to treatment. Sixteen patients (50%) underwent dose escalation. Treatment was well tolerated, with only one patient (3.1%) in the standard treatment group experiencing acute Grade 3 diarrhea, proctitis, and cystitis. No significant differences in toxicity were observed between the two groups (p = 0.5463).ConclusionsMRIgRT treatment with dose escalation up to 60.1 Gy is well tolerated in LARC patients predicted as non-responders by ERI, confirming the feasibility and safety of this approach. The THUNDER-2 trial’s primary and secondary endpoints will be fully analyzed when all planned patients will be enrolled.

Correlation between Lymph Node Regression Grading and Tumor Regression Grading after Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

This study aimed to determine the relationship between tumor regression grading (TRG) and lymph node regression grading (LRG) after neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC). The study was a retrospective analysis of the clinical data of LARC patients who underwent preoperative nCRT at one institution. A total of 101 rectal cancer patients who received nCRT and underwent total rectal mesenteric excision (TME) were included. Pathologists independently assessed the pathological response of the primary tumor and lymph nodes (LN) to nCRT using TRG and LRG, respectively. The highest LRG score for each patient was defined as LRGmax, and LRGsum was the overall tumor burden of all LNs in the specimen. The study included 101 LARC patients who underwent nCRT and TME. The patient population consisted of 65 males and 36 females with an average age of 54.86 years (range 20-81 years), of which 68 were aged 60 years or younger and 33 were older than 60. The radiotherapy treatment plan consisted of 1.8-2Gy per dose, administered 5 times per week for a total dose of 45-50.4Gy, along with oral capecitabine chemotherapy (825 mg/m2, bid) on the day of radiation therapy. The chemotherapy treatment plan included XELOX, mFOLFOX6, and FOLFOX4. The cTNM stage of the tumor before surgery was cT2 in 2 cases, cT3 in 63 cases, and cT4 in 36 cases. Eight cases were cN0 and 93 were cN+. After surgery, the ypTNM stage was T0 in 19 cases, T1 in 4 cases, T2 in 27 cases, T3 in 45 cases, and T4 in 6 cases. The N stage was N0 in 76 cases, N1 in 20 cases, and N2 in 5 cases. TRG was 0 in 17 cases (16.8%), 1 in 15 cases (14.9%), 2 in 61 cases (60.4%), and 3 in 8 cases (7.9%). LRGmax scores were 0 in 66 cases (65.3%), 1 in 17 cases (16.8%), 2 in 5 cases (5.0%), 3 in 3 cases (3.0%), 4 in 5 cases (5.0%), and 5 in 5 cases (5.0%). LRGsum scores were ≤3 in 85 cases (84.2%), 4-9 in 11 cases (10.9%), and ≥10 in 5 cases (5.0%). Correlation analysis showed that LRGmax was significantly correlated with TRG, ypT, and ypN (P = 0.038, P = 0.015, P < 0.01), with correlation coefficients of 0.184, 0.212, and 0.626, respectively. There was no significant correlation between LRGmax and cT and cN+. Similarly, LRGsum was significantly correlated with TRG, ypT, and ypN (P = 0.022, P = 0.002, P < 0.01) with correlation coefficients of 0.212, 0.276, and 0.707, respectively. There was no significant correlation between LRGsum and cT and cN. The results of our study indicate a significant correlation between LRG and TRG (P = 0.022). Additionally, LRG was found to be positively correlated with the ypT and ypN stages of the primary tumor and lymph nodes post-surgery, with correlation coefficients of 0.276 and 0.707, respectively (P = 0.002 and P<0.01). No significant correlations were observed between LRG and cT and cN+ stages. Our findings demonstrate a significant association between LRG and TRG, as well as a positive correlation between LRG and the ypT and ypN stages of the primary tumor and lymph nodes following surgery.

Outcomes and Failure Patterns after Chemoradiotherapy for Locally Advanced Rectal Cancer with Positive Lateral Pelvic Lymph Nodes: A Propensity Score-Matched Analysis

Locally advanced rectal cancer (LARC) combined with positive lateral pelvic lymph nodes (LPLN) tends to present worse prognosis. However, for those patients it remains unclear whether other combination high-risk factors affect the prognosis. This study aimed to use propensity score matching (PSM) to examine long-term outcomes and failure patterns in patients with positive vs. negative LPLN. Patients with LARC were retrospectively divided into LPLN-positive and LPLN-negative groups. LPLN-positivity was defined as lymph node short diameter greater than or equal to 7 mm with specific morphological features. Clinical characteristics were compared between the groups using the chi-square test. PSM was applied to balance these differences. Progression-free survival (PFS) and overall survival (OS), and local-regional recurrence (LRR) and distant metastasis (DM) rates were compared between the groups using the Kaplan-Meier method and log-rank tests. Prior to PSM, a total of 651 LARC patients were included. The LPLN-positive group had higher rates of lower location (53.1% vs. 43.0%, P = 0.025), mesorectal fascia (MRF)-positive (53.9% vs. 35.4%, P<0.001) and extramural venous invasion (EMVI)-positive (51.2% vs. 27.2%, P<0.001) disease than the LPLN-negative group. After PSM, there were 114 patients for each group along with the balanced clinical factors, and both groups had comparable surgery, pathologic complete response (pCR), and ypN stage rates. The median follow-up time was 45.9 months, 3-year OS (88.3% vs. 92.1%, P = 0.276) and LRR (5.7% vs. 2.8%, P = 0.172) rates were comparable between LPLN-positive and LPLN-negative groups. Meanwhile, despite no statistical difference, 3-year PFS (78.8% vs. 85.9%, P = 0.065) and DM (20.4% vs. 13.3%, P = 0.061) rates slightly differed between the groups. Among 10 patients with LRR, seven (70.0%) had lateral pelvic recurrence, among them, five patients were LPLN-positive, and four (80.0%) of these patients did not receive simultaneous integrated boost intensity-modulated radiotherapy (SIB- IMRT).45 patients were diagnosed with DM, 11 (40.7%) LPLN-positive and 3 (17.6%) LPLN-negative patients were diagnosed with oligometastases (P = 0.109). Our study shows there is a tendency of worse PFS and DM in LPLN-positive than LPLN-negative patients, for LPLN-positive patients, oligometastases account for a large proportion of all distant metastases.

An Immune-Related Gene Prognostic Prediction Risk Model for Neoadjuvant Chemoradiotherapy in Rectal Cancer Using Artificial Intelligence

To develop and validate an immune-related gene prognostic model (IRGPM) that can predict disease-free survival (DFS) in patients with locally advanced rectal cancer (LARC) who received neoadjuvant chemoradiotherapy and to clarify the immune characteristics of patients with different prognostic risks. In this study, we obtained transcriptomic and clinical data from the Gene Expression Omnibus (GEO) database and rectal cancer database of West China Hospital. Genes in the RNA immune-oncology panel were extracted. Elastic net was used to identify the immune-related genes that significantly affected the DFS of patients. A prognostic risk model (IRGPM) for rectal cancer was constructed with the random forest method. The prognostic risk score was calculated by the model, and the patients were divided into high- and low-risk groups according to the median risk score. Immune characteristics were analyzed and compared between the high- and low-risk groups. A total of 407 LARC samples were used in this study. A 20-gene signature was identified by elastic net and was found to be significantly correlated with DFS. The IRGPM was constructed on the basis of the 20 immune-related genes. Kaplan‒Meier survival analysis showed poorer 5-year DFS in the high-risk group than in the low-risk group, and the receiver operating characteristic (ROC) curve suggested good model prediction (areas under the curve (AUCs) of 0.87, 0.94, 0.95 at 1, 3, and 5 years, respectively). The model was validated in the GSE190826 cohort (AUCs of 0.79, 0.64, and 0.63 at 1, 3, and 5 years, respectively) and the cohort from our institution (AUCs of 0.64, 0.66, and 0. 64 at 1, 3, and 5 years, respectively). The differentially expressed genes between the high- and low-risk groups were enriched in cytokine‒cytokine receptor interactions. The patients in the low-risk group had higher immune scores than the patients in the high-risk group. Subsequently, we found that activated B cells, activated CD8 T cells, central memory CD8 T cells, macrophages, T follicular helper cells and type 2 helper cells were more abundant in the low-risk group. Moreover, we compared the expression of immune checkpoints and found that the low-risk group had a higher PDCD1 expression level. The IRGPM, which was constructed based on the random forest and elastic net methods, is a promising method to distinguish DFS in LARC patients treated with a standard strategy. The low-risk group identified by IRGPM was characterized by the activation of adaptive immunity in tumor microenvironment.

Cost-Effectiveness of Short-Course Radiotherapy Based Total Neoadjuvant Therapy for Locally Advanced Rectal Cancer in China

The phase III STELLAR (NCT02533271) trial demonstrated that four cycles of chemotherapy after short-course radiotherapy (SCRT-TNT) were not inferior to the standard care of long-course concurrent radiotherapy (LCRT) in patients with locally advanced rectal cancer (LARC). This study assessed the cost-effectiveness of SCRT-TNT versus LCRT in locally advanced rectal cancer in China on the basis of the STELLAR trial. A Markov model was used to synthesize the healthcare costs and benefits of LARC patients based on results from the STELLAR trial. The model assumes that LARC who meet the inclusion criteria of the STELLAR trial experience four possible states: No Evidence of Disease (NED), locally recurrence, distant metastases, or any death from rectal cancer or other unrelated causes, where local recurrence continues to be classified as resectable and unresectable. The transition status period is 3 month, and 5 years is used to calculate direct medical costs and health benefits. The probabilities of states transition after SCRT-TNT or LCRT were derived from the results of the STELLAR trial and previous published article (Table.1). Costs were evaluated from the Chinese payer's perspective reported in early 2022 US dollars (US$1 = 6.78 Chinese Yuan). Sensitivity analyses were performed for key variables. Cost-effectiveness was evaluated using the incremental cost-effectiveness ratio and net monetary benefits. Effectiveness was defined as quality-adjusted life-years (QALYs). Willingness-to-pay (WTP) threshold was set at $43500/QALY. Data were collected from October 3, 2020, to September 20, 2021, and analyzed from November 15, 2020, to October 25, 2021. During the 5-year horizon, for the base case scenario, SCRT-TNT incurred a lower total cost and higher QALYs compared with LCCRT. The total cost was $65767 and QALYs were 1.77 for SCRT-TNT; for LCCRT, the total cost was $72802 and QALYs were 1.64. This resulted in an ICER of -$ 55470.69 per QALY. Therefore, SCRT-TNT was a cost-saving and dominating treatment strategy compared with LCRT. Sensitivity analysis showed that ICERs were most sensitive to the parameters of distant metastases risk after treatment. SCRT-TNT in locally advanced rectal cancer can be a cost-effective alternative to LCRT in China, and should be considered in appropriately selected patients.

Fully automated volumetric modulated arc therapy planning for locally advanced rectal cancer: feasibility and efficiency

BackgroundVolumetric modulated arc therapy (VMAT) for locally advanced rectal cancer (LARC) has emerged as a promising technique, but the planning process can be time-consuming and dependent on planner expertise. We aimed to develop a fully automated VMAT planning program for LARC and evaluate its feasibility and efficiency.MethodsA total of 26 LARC patients who received VMAT treatment and the computed tomography (CT) scans were included in this study. Clinical target volumes and organs at risk were contoured by radiation oncologists. The automatic planning program, developed within the Raystation treatment planning system, used scripting capabilities and a Python environment to automate the entire planning process. The automated VMAT plan (auto-VMAT) was created by our automated planning program with the 26 CT scans used in the manual VMAT plan (manual-VMAT) and their regions of interests. Dosimetric parameters and time efficiency were compared between the auto-VMAT and the manual-VMAT created by experienced planners. All results were analyzed using the Wilcoxon signed-rank sum test.ResultsThe auto-VMAT achieved comparable coverage of the target volume while demonstrating improved dose conformity and uniformity compared with the manual-VMAT. V30 and V40 in the small bowel were significantly lower in the auto-VMAT compared with those in the manual-VMAT (p < 0.001 and < 0.001, respectively); the mean dose of the bladder was also significantly reduced in the auto-VMAT (p < 0.001). Furthermore, auto-VMAT plans were consistently generated with less variability in quality. In terms of efficiency, the auto-VMAT markedly reduced the time required for planning and expedited plan approval, with 93% of cases approved within one day.ConclusionWe developed a fully automatic feasible VMAT plan creation program for LARC. The auto-VMAT maintained target coverage while providing organs at risk dose reduction. The developed program dramatically reduced the time to approval.

The impact of extended waiting time on tumor regression after neoadjuvant chemoradiotherapy for locally advanced rectal cancer

Objective: To investigate the influence of extending the waiting time on tumor regression after neoadjuvant chemoradiology (nCRT) in patients with locally advanced rectal cancer (LARC). Methods: Clinicopathological data from 728 LARC patients who completed nCRT treatment at the First Affiliated Hospital, Naval Medical University from January 2012 to December 2021 were collected for retrospective analysis. The primary research endpoint was the sustained complete response (SCR). There were 498 males and 230 females, with an age (M(IQR)) of 58 (15) years (range: 22 to 89 years). Logistic regression models were used to explore whether waiting time was an independent factor affecting SCR. Curve fitting was used to represent the relationship between the cumulative occurrence rate of SCR and the waiting time. The patients were divided into a conventional waiting time group (4 to <12 weeks, n=581) and an extended waiting time group (12 to<20 weeks, n=147). Comparisons regarding tumor regression, organ preservation, and surgical conditions between the two groups were made using the t test, Wilcoxon rank sum test, or χ2 test as appropriate. The Log-rank test was used to elucidate the survival discrepancies between the two groups. Results: The SCR rate of all patients was 21.6% (157/728). The waiting time was an independent influencing factor for SCR, with each additional day corresponding to an OR value of 1.010 (95%CI: 1.001 to 1.020, P=0.031). The cumulative rate of SCR occurrence gradually increased with the extension of waiting time, with the fastest increase between the 10th week. The SCR rate in the extended waiting time group was higher (27.9%(41/147) vs. 20.0%(116/581), χ2=3.901, P=0.048), and the organ preservation rate during the follow-up period was higher (21.1%(31/147) vs. 10.7%(62/581), χ2=10.510, P=0.001). The 3-year local recurrence/regrowth-free survival rates were 94.0% and 91.1%, the 3-year disease-free survival rates were 76.6% and 75.4%, and the 3-year overall survival rates were 95.6% and 92.2% for the conventional and extended waiting time groups, respectively, with no statistical differences in local recurrence/regrowth-free survival, disease-free survival and overall survival between the two groups (χ2=1.878, P=0.171; χ2=0.078, P=0.780; χ2=1.265, P=0.261). Conclusions: An extended waiting time is conducive to tumor regression, and extending the waiting time to 12 to <20 weeks after nCRT can improve the SCR rate and organ preservation rate, without increasing the difficulty of surgery or altering the oncological outcomes of patients.

Deep learning of endoscopic features for the assessment of neoadjuvant therapy response in locally advanced rectal cancer.

For locally advanced rectal cancer (LARC), accurate response evaluation is necessary to select complete responders after neoadjuvant therapy (NAT) for a watch-and-wait (W&W) strategy. Algorithms based on deep learning have shown great value in medical image analyses. Here we used deep learning algorithms of endoscopic images for the assessment of NAT response in LARC. 214 LARC patients were retrospectively included in the study. After NAT, these patients underwent total mesorectal excision (TME) surgery. Among them, 51 (23.8%) of the patients achieved a pathological complete response (pCR). 160 patients from Shanghai Changzheng Hospital were regarded as primary dataset, and the other 54 patients from Zhejiang Cancer Hospital were regarded as validation dataset. ResNet-18 and DenseNet-121 were applied to train the models based on endoscopic images after NAT. Deep learning models were valid in the validation dataset and compared to manual method. The performances were comparable in AUC between deep learning models and manual method. For mean metrics, sensitivity (0.750 vs. 0.417) and AUC (0.716 vs. 0.601) in ResNet-18 deep learning model were higher than those in the manual method. The deep learning models were able to identify the endoscopic features associated with NAT response by the heatmaps. A diagnostic flow diagram which integrated the deep learning model to assist the clinicians in making decisions for W&W strategy was constructed. We created deep learning models using endoscopic features for assessment of NAT in LARC. The deep learning models achieved modest accuracies and performed comparably to manual method.

Use of patient-derived tumor organoid platform to predict the benefit of postoperative adjuvant chemotherapy for poor responders to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Postoperative adjuvant chemotherapy (AC) for poor responders to neoadjuvant chemoradiotherapy (nCRT) remains debatable among patients with locally advanced rectal cancer (LARC), necessitating biomarkers to accurately predict the benefits of AC. This study aimed to develop a patient-derived tumor organoid (PDTO) platform to predict the benefit of AC in LARC patients showing poor nCRT response. PDTOs were established using irradiated rectal cancer specimens with poor nCRT responses, and their sensitivity to chemotherapy regimens was tested. The half-maximal inhibitory concentration (IC50) value for the PDTO drug test was defined based on the clinical outcomes, and the accuracy of the PDTO prognostic predictions was calculated. Predictive models were developed and validated using the PDTO drug test results. Between October 2018 and December 2021, 86 PDTOs were successfully constructed from 138 specimens (success rate 62.3%). The optimal IC50 cut-off value for the organoid drug test was 39.31 μmol/L, with a sensitivity of 84.75%, a specificity of 85.19%, and an accuracy of 84.88%. Multivariate Cox regression analysis revealed that the PDTO drug test was an independent predictor of prognosis. A nomogram based on the PDTO drug test was developed, showing good prognostic ability in predicting the 2-year and 3-year disease-free survivals (AUC of 0.826 [95% CI, 0.721-0.931] and 0.902 [95% CI, 0.823-0.982], respectively) and overall survivals (AUC of 0.859 [95% CI, 0.745-0.973] and 0.885 [95% CI, 0.792-0.978], respectively). The PDTO drug test can predict the benefit of postoperative AC in poor responders with LARC to nCRT.

A multiple-time-scale comparative study for the added value of magnetic resonance imaging-based radiomics in predicting pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

Radiomics based on magnetic resonance imaging (MRI) shows potential for prediction of therapeutic effect to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC); however, thorough comparison between radiomics and traditional models is deficient. We aimed to construct multiple-time-scale (pretreatment, posttreatment, and combined) radiomic models to predict pathological complete response (pCR) and compare their utility to those of traditional clinical models. In this research, 165 LARC patients undergoing nCRT followed by surgery were enrolled retrospectively, which were divided into training and testing sets in the ratio of 7:3. Morphological features on pre- and posttreatment MRI, coupled with clinical data, were evaluated by univariable and multivariable logistic regression analysis for constructing clinical models. Radiomic parameters were derived from pre- and posttreatment T2- and diffusion-weighted images to develop the radiomic signatures. The clinical-radiomics models were then generated. All the models were developed in the training set and then tested in the testing set, the performance of which was assessed using the area under the receiver operating characteristic curve (AUC). Radiomic models were compared with the clinical models with the DeLong test. One hundred and sixty-five patients (median age, 55 years; age interquartile range, 47-62 years; 116 males) were enrolled in the study. The pretreatment maximum tumor length, posttreatment maximum tumor length, and magnetic resonance tumor regression grade were selected as independent predictors for pCR in the clinical models. In the testing set, the pre- and posttreatment and combined clinical models generated AUCs of 0.625, 0.842, and 0.842 for predicting pCR, respectively. The MRI-based radiomic models performed reasonably well in predicting pCR, but neither the pure radiomic signatures (AUCs, 0.734, 0.817, and 0.801 for the pre- and posttreatment and combined radiomic signatures, respectively) nor the clinical-radiomics models (AUCs, 0.734, 0.860, and 0.801 for the pre- and posttreatment and combined clinical-radiomics models, respectively) showed significant added value compared with the clinical models (all P > 0.05). The MRI-based radiomic models exhibited no definite added value compared with the clinical models for predicting pCR in LARC. Radiomic models can serve as ancillary tools for tailoring adequate treatment strategies.

Early Age of Onset Is an Independent Predictor for a Worse Response to Neoadjuvant Therapies in Sporadic Rectal Cancer Patients.

The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0-2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients.

Prognostic ability of the neoadjuvant rectal (NAR) score in long‐course concurrent chemoradiotherapy for patients with locally advanced rectal cancer: a retrospective cohort study

AbstractBackgroundThe aims of this study were to evaluate the prognostic ability of the neoadjuvant rectal (NAR) score and to develop and validate a nomogram based on the NAR for patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT).MethodsIn total, 307 patients, including 230 patients from the primary cohort and 77 from the external cohort, were enrolled across the two centers. The associations of the NAR score with the tumor response, tumor control, and clinicopathological parameters were analyzed. Survival analysis was performed in the primary and external cohorts using Kaplan‒Meier curves. Univariate and multivariate analyses were performed to evaluate the prognostic factors. The NAR‐based nomogram was developed in the primary cohort and validated in the external cohort using the concordance index (C‐index), calibration plots, and decision curve analyses (DCAs).ResultsKaplan‒Meier survival analysis revealed that the disease‐free survival (DFS) and overall survival (OS) of the NAR &gt; 16 group were significantly lower than those of the NAR ≤ 16 group (p &lt; 0.001). Multivariate Cox regression analysis identified the NAR score as an independent prognostic factor for both DFS (hazard ratio [HR] = 2.484, 95% confidence interval [CI]: 1.159−5.323, p = 0.019) and OS (HR = 4.633, 95% CI: 1.076−19.941, p = 0.04). Calibration plots and DCAs showed that NAR‐based nomograms for DFS and OS were consistent and useful in clinical practice. Moreover, the C‐indexes of the NAR‐based nomograms were better than those of the other variables in both the primary and external cohorts.ConclusionOur study validates the prognostic role of the NAR score for DFS and OS. The NAR‐based nomogram for OS could accurately predict the outcome of LARC patients by stratifying the risk score accordingly.

Total Neoadjuvant Therapy (TNT) with Full Dose Concurrent Chemotherapy in Locally Advanced Rectal Adenocarcinoma Including Signet Ring and Mucinous Cancers.

Total neoadjuvant therapy (TNT) with pre-operative chemotherapy and chemoradiotherapy results in improved survival and is becoming the new standard of care in locally advanced rectal cancer (LARC). We describe our experience with TNT consisting of induction chemotherapy followed by chemoradiotherapy using full dose 5FU without oxaliplatin. Adults with biopsy-proven, newly diagnosed LARC with high-risk characteristics on pelvic MRI (T4a or T4b, extramural vascular invasion, N2, mesorectal fascia involvement, enlargement/tumor deposits on lateral lymph nodes) were included. The TNT protocol comprised of six biweekly courses of modified FOLFOX6 followed by pelvic RT with four concurrent cycles of biweekly 5-FU 2600mg/m2 + LV 200mg/m2 without oxaliplatin to complete 20 uninterrupted weeks of full dose 5FU. Surgery was planned 11-13weeks after completing chemoradiotherapy. Eighty-four LARC patients, including 26% with signet-ring cell carcinoma, with high-risk MRI characteristics were treated with the TNT protocol with a 96% completion rate. Significant (> grade 3) toxicities included neutropenia (23.8%), diarrhea (14.2%) anemia (10.7%), and two deaths. The median DFS at 2years was 22.5months with better survival noted for those who underwent surgery or had cCR (with NOM) compared to those who did not undergo surgery (due to progression, inadequate regression, or patient preference despite residual disease) -mDFS 27.7months versus 11.4months, p = < 0.0001 and mOS 29.2months versus 15months p = < 0.0001. The hybrid TNT regimen was administered without significant dose delays or interruptions. Toxicity was manageable but with two treatment-related deaths. Ability to undergo surgery after TNT predicted for improved DFS and OS.

CD11c+ and IRF8+ cell densities in rectal cancer biopsies predict outcomes of neoadjuvant chemoradiotherapy

ABSTRACT Approximately 20% of locally advanced rectal cancer (LARC) patients treated preoperatively with chemoradiotherapy (CRT) achieve pathologically confirmed complete regression. However, there are no clinically implemented biomarkers measurable in biopsies that are predictive of tumor regression. Here, we conducted multiplexed immunophenotyping of rectal cancer diagnostic biopsies from 16 LARC patients treated preoperatively with CRT. We identified that patients with greater tumor regression had higher tumor infiltration of pan-T cells and IRF8+HLA-DR+ cells prior to CRT. High IRF8+HLA-DR+ cell density was further associated with prolonged disease-specific survival with 83% survival at 5 y compared to 28% in patients with low infiltration. Contrastingly, low CD11c+ myeloid cell infiltration prior to CRT was a putative biomarker associated with longer 3- and 5-y disease-free survival. The results demonstrate the potential use of rectal cancer diagnostic biopsies to measure IRF8+ HLA-DR+ cells as predictors of CRT-induced tumor regression and CD11c+ myeloid cells as predictors of LARC patient survival.

Neoadjuvant S-1 and oxaliplatin plus bevacizumab therapy for high-risk locally advanced rectal cancer: A prospective multicenter phase II study.

We report the short/mid-term results of surgery for high-risk locally advanced rectal cancer (LARC) after neoadjuvant chemotherapy (NAC, four courses of S-1 + oxaliplatin+ bevacizumab) without radiotherapy with the primary aim of ypT0-2. High-risk LARC was defined as cT4b, mesorectal fascia (MRF) ≤1 mm (MRF+), or lateral lymph node metastasis (cLLN+) on high-resolution MRI. The planned 32 cases from April 2018 to December 2021 were all included. There were 10 patients at cT4b (31.2%), 26 MRF+ (81.3%), and 22 cLLN+ (68.8%). Thirteen (40.6%) underwent NAC after a colostomy for stenosis. NAC was completed in 26 (81.2%) cases. Grade 3 or higher adverse events occurred in six (18.7%). One patient developed progressive disease (3.2%). Eleven were ycT0-3MRF-LLN- (34.3%). Curative-intent surgery was performed on 31, with sphincter-preserving surgery in 20, abdominoperineal resection in nine, total pelvic exenteration in two, and lateral lymph node dissection in 24. Two had R1/2 resection (6.4%). A Grade 3 or higher postoperative complication rate occurred in 3.2%. Pathological complete response and ypT0-2 rates were 12.9% and 45.1%. Three-year disease-free survival rates (3yDFS) for ypT0-2 and ypT ≥3 were 81.2%, 46.6% (p = 0.061), and 3-year local recurrence rates (3yLR) were 0%, 48.8% (p = 0.015). 3yDFS for ycT0-3MRF-LLN- and ycT4/MRF+/LLN+ were 87.5%, 48.0% (p = 0.031) and 3yLR were 0%, 42.8% (p = 0.045). NAC yielded a clinically significant effect in about half of high-risk LARC patients. If NAC alone is ineffective, radiotherapy should be added, even if extended surgery is intended.

“Long-term oncologic outcomes and risk factors for distant recurrence after pathologic complete response following neoadjuvant treatment for locally advanced rectal cancer. A nationwide, multicentre study”

BackgroundPathologic complete response (pCR) after multimodal treatment for locally advanced rectal cancer (LARC) is used as surrogate marker of success as it is assumed to correlate with improved oncologic outcome. However, long-term oncologic data are scarce. MethodsThis retrospective, multicentre study updated the oncologic follow-up of prospectively collected data from the Spanish Rectal Cancer Project database. pCR was described as no evidence of tumour cells in the specimen. Endpoints were distant metastases-free survival (DMFS) and overall survival (OS). Multivariate regression analyses were run to identify factors associated with survival. ResultsOverall, 32 different hospitals were involved, providing data on 815 patients with pCR. At a median follow-up of 73.4 (IQR 57.7–99.5) months, distant metastases occurred in 6.4% of patients. Abdominoperineal excision (APE) (HR 2.2, 95%CI 1.2–4.1, p = 0.008) and elevated CEA levels (HR = 1.9, 95% CI 1.0–3.7, p = 0.049) were independent risk factors for distant recurrence. Age (years) (HR 1.1; 95%-CI 1.05–41.09; p < 0.001) and ASA III-IV (HR = 2.0; 95%-CI 1.4–2.9; p < 0.001), were the only factors associated with OS. The estimated 12, 36 and 60-months DMFS rates were 96.9%, 91.3%, and 86.8%. The estimated 12, 36 and 60-months OS rates were 99.1%, 94.9% and 89.3%. ConclusionsThe incidence of metachronous distant metastases is low after pCR, with high rates of both DMFS and OS. The oncologic prognosis in LARC patients that achieve pCR after neoadjuvant chemo-radiotherapy is excellent in the long term.